The ubiquitin ligase Siah2 regulates tumorigenesis and metastasis by HIF-dependent and -independent pathways.
The ubiquitin ligase Siah2 has been shown to regulate prolyl hydroxylase 3 (PHD3) stability with concomitant effect on HIF-1alpha availability. Because HIF-1alpha is implicated in tumorigenesis and metastasis, we used SW1 mouse melanoma cells, which develop primary tumors with a propensity to metastasize, in a syngeneic mouse model to assess a possible role for Siah2 in these processes. Inhibiting Siah2 activity by expressing a peptide designed to outcompete association of Siah2-interacting proteins reduced metastasis through HIF-1alpha without affecting tumorigenesis. Conversely, inhibiting Siah2 activity by means of a dominant-negative Siah2 RING mutant primarily reduced tumorigenesis through the action of Sprouty 2, a negative regulator of Ras signaling. Consistent with our findings, reduced expression of PHD3 and Sprouty2 was observed in more advanced stages of melanoma tumors. Using complementary approaches, our data establish the role of Siah2 in tumorigenesis and metastasis by HIF-dependent and -independent mechanisms.
Qi
Jianfei
J
Signal Transduction and Cell Death Programs, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Nakayama
Koh
K
Gaitonde
Supriya
S
Goydos
James S
JS
Krajewski
Stan
S
Eroshkin
Alexey
A
Bar-Sagi
Dafna
D
Bowtell
David
D
Ronai
Ze'ev
Z
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008546:Melanoma, Experimental / Q000209:etiology* / Q000473:pathology; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis; D011393:Procollagen-Proline Dioxygenase / Q000032:analysis / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C522722:PHD3 protein, mouse; D011393:Procollagen-Proline Dioxygenase; C533102:Siah2 protein, mouse; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse; D018631:ras Proteins